Abstract

Background and Purpose The durability of carotid endarterectomy (CEA) in young adults with premature carotid atherosclerosis has not been adequately assessed. This study examined the late recurrence and mortality rates in young adults undergoing CEA.

Results Demographics and atherosclerotic risk factors were similar between the two groups. During a mean follow-up of 57.9±6.0 months, 10 (24%) young patients and 3 (3%) control subjects developed significant, recurrent ipsilateral stenoses (≥50% diameter loss) (P<.001). Six (14%) young patients and 1 control subject had recurrent ipsilateral symptoms (P=.002). Nine (21%) young patients and 26 (24%) older control subjects required contralateral CEA; 8 (18%) young patients and 18 (16%) older control subjects underwent lower extremity revascularization procedures. Cumulative 5-year survival by life-table analysis was 0.83 (95% confidence interval [CI], 0.71 to 0.95) for study patients and was 0.67 (95% CI, 0.58 to 0.77) for control subjects (P=.06).

Conclusions These data demonstrate a trend toward more favorable survival in young versus older patients after CEA; however, survival differences did not achieve statistical significance. Young patients are far more likely to develop recurrent symptoms and recurrent carotid stenoses than older counterparts. Close follow-up with serial duplex ultrasound may be important in young patients after CEA.

Premature (early onset) atherosclerosis has been considered a virulent form of arterial disease. Reports of young adults with premature atherosclerosis in the lower extremity circulation have demonstrated a rapid progression of disease,12 a high incidence of amputation due to graft failure,34 and decreased survival.5 The prognosis of young adults with premature CA is less well understood, and the outcome of CEA in young patients with CA has not been reported.

CA is considered to be an infrequent cause of stroke in young adults. It has been estimated that premature CA accounts for 20% to 33% of cerebral infarctions in patients aged 15 to 49 years.6789 However, mortality and recurrent cerebrovascular symptoms are more likely in young patients with strokes due to CA compared with those with strokes due to other causes.101112 Although recent multicenter trials have documented the value of CEA in reducing strokes and death among patients with compelling lesions,1314 the value of CEA in young adults compared with older individuals with CA is unknown. Scant data regarding premature CA suggest that youth may be a risk factor for carotid restenosis after CEA,15 but whether this is associated with recurrent symptoms, especially stroke, and decreased survival is unknown. On the basis of reports of patients with premature atherosclerosis in other locations,12345 we hypothesized that young patients have a worse prognosis than older counterparts after CEA. The following study was performed to examine the rate of carotid recurrence, the progression of peripheral atherosclerosis, and the late mortality in young versus older patients after CEA.

Subjects and Methods

Patients

We studied all patients aged 49 years and younger who underwent CEA at our institutions during the years 1980 through 1994. We performed approximately 680 CEAs in patients of all ages during this period. Patients who were lost to follow-up within 1 year of discharge and those who did not have at least two postoperative noninvasive tests were excluded from the analysis. A total of 48 patients aged 49 years and younger underwent CEA during the study period, and 6 of these were excluded. The remaining 42 patients composed the present study group. Fifteen patients (36%) underwent CEA from 1980 through 1985; 13 (31%) underwent CEA from 1986 through 1989; and 14 (33%) underwent CEA from 1990 through 1994. All endarterectomy specimens were determined to be atherosclerotic in origin by pathological examination. Medical records were reviewed for demographic data, presence of atherosclerotic risk factors, surgical indications, and operative details. Follow-up data were obtained from telephone interviews and from records of outpatient clinic visits, vascular laboratory reports, subsequent hospital admissions, and autopsy reports. Details of subsequent vascular operations were also noted.

Control Subjects

For comparison purposes, we also studied 110 older patients aged 60 to 80 years who underwent CEA during the same period. These control subjects were obtained from a group of 170 consecutive patients aged 50 years and older who were entered into a prospective protocol evaluating the use of CEA patch closure16 or who were participants randomized to CEA in the North American Symptomatic Carotid Endarterectomy Trial13 and the Asymptomatic Carotid Atherosclerosis Study.14 Patients from these study protocols were chosen for control subjects because they underwent thorough and meticulous follow-up assessment and serial duplex ultrasonography. We specifically excluded 60 patients aged 50 to 59 years to avoid age overlap between younger and older subjects, allowing a more meaningful assessment of the impact of age on outcome. Demographics, risk factors, and survival of the excluded patients were not significantly different from those selected as controls. Forty-two control subjects (38%) underwent CEA from 1980 through 1985; 50 (45%) underwent CEA from 1986 through 1989; and 18 (16%) underwent CEA from 1990 through 1994. The distribution of CEA procedures between the three time periods was not significantly different from that of young patients.

Postoperative Surveillance

All subjects underwent routine examinations and noninvasive studies according to our standard protocol,16 which included evaluations every 3 months for 1 year and every 6 months thereafter with history, physical examination, and carotid duplex scans. Until 1987, duplex scanning was performed with the Diasonics DS10 model. After 1987, duplex scans were performed with the ATL Ultramark IV scanner (Advanced Technology Laboratories) or the Acuson 128XP sonography system. Plaque imaging and sound spectral analysis or calculated velocity flow were used to determine degree of stenosis as previously described, and carotid stenoses were graded according to standardized criteria.17 For purposes of this study, we considered stenoses associated with a luminal diameter loss of ≥50% to be significant. We defined a residual carotid stenosis as one found within the first 3 months of operation. A recurrent carotid stenosis was defined as one appearing after the 3-month postoperative duplex examination that was present on at least two subsequent examinations.

Descriptive results are expressed as mean±SEM. The χ2 test was used to perform statistical comparisons between categorical parameters. The unpaired Student's t test was used to compare groups of unpaired data. Results were considered significant at the P<.05 level. Life-table analysis was used to estimate survival and recurrence-free intervals by the Kaplan-Meier method.18 In determination of recurrence-free intervals, death was considered to be in the same censored category as lost to follow-up.

Results

The mean age of the 42 young patients was 45.5±0.5 years (range, 37 to 49 years). Three (7%) of the young patients were 40 years of age or younger. The mean age of the older control subjects was 65.8±0.4 years (range, 60 to 79 years). Demographic data and prevalence of atherosclerotic risk factors among young patients and control subjects are shown in Table 1⇓. Eighteen (43%) of the young patients had symptoms of coronary heart disease, as did 54 (49%) of the controls. Forty (96%) of the young patients underwent CEA for TIA or strokes, and two (4%) underwent CEA for advanced asymptomatic carotid stenoses (Table 1⇓). In comparison, 87 (79%) of the control subjects underwent CEA for TIA or strokes, and 23 (21%) were asymptomatic (P=.02). Twenty (48%) of the young patients and 12 (11%) of the controls had documented strokes before CEA (P<.001).

There were no perioperative strokes at the time of initial CEA in young patients. Three (2.7%) of the older control subjects had minor (no lasting neurological deficit) strokes within 30 days of initial CEA. The mean follow-up time for the young patients was 57.9±6.0 months, which was not significantly different from 52±3 months for the controls. None of the study patients or controls had a residual carotid stenosis.

Ten young patients (24%) developed recurrent carotid stenoses or carotid occlusions during a mean of 48±7 months. Degree of restenosis is shown in Table 2⇓. Four of the 10 young patients who developed recurrences had undergone patch angioplasty during the original CEA, and 6 had undergone primary closure. Two of the 10 recurrences occurred within 2 years of CEA, and 8 occurred after 2 years. Six of the 10 patients had recurrent symptoms; 5 had recurrent TIAs and 1 had a stroke. There were no recurrent symptoms among young patients who did not have recurrent stenoses. Comparing the 10 young patients who developed recurrent stenoses to the 32 who did not, we found no differences in mean age of onset (46±1 years versus 44±1 years), smoking after CEA (90% versus 91%), hypertension (70% versus 75%), diabetes mellitus (20% versus 22%), or mean number of risk factors (2.2 versus 2.3). In contrast, 3 (3%) of the control subjects developed recurrent stenoses or carotid occlusions during a mean of 39±8 months (P<.001). All three recurrences among control subjects were detected later than 2 years after CEA. Two of the 3 controls who developed recurrences had undergone patch angioplasties at the time of the original CEA, and 1 had undergone primary closure. Two of the 3 controls with recurrences were asymptomatic, and 1 had recurrent TIA symptoms. None of the 107 controls without recurrent stenoses developed recurrent symptoms. By life-table analysis, 72% of surviving young patients and 97% of surviving control subjects were recurrence-free at 5 years (P<.001) (Fig 1⇓).

Among the 10 young patients who developed recurrent carotid stenoses, 3 underwent reoperative CEA (Table 3⇓). The indication for operation was recurrent TIA symptoms associated with a 70% stenosis in 2 and an asymptomatic 95% stenosis in the third. Two other young patients refused operation; 1 had recurrent TIA symptoms associated with an 80% stenosis, and the other had an asymptomatic 80% stenosis. Both patients died of myocardial infarctions within 1 year of discovery of the recurrent carotid disease. Two other patients with recurrent carotid stenoses were lost to follow-up.

Three of the 10 young patients who developed recurrent disease had carotid occlusions. All 3 of these patients missed routine surveillance appointments. In 2 cases, carotid occlusions were found 1 year after <50% stenoses had been documented by duplex ultrasonography. The third carotid occlusion was detected 18 months after duplex ultrasonography had documented minimal plaque disease.

Two of the 3 control subjects underwent reoperative CEA; the third had a carotid occlusion. Indications for operation were recurrent symptoms associated with a 65% stenosis in 1 and an asymptomatic 95% stenosis in the other.

During follow-up, 9 (21%) young patients and 26 (24%) control subjects required contralateral CEA (Table 2⇑). Eight (19%) of the young patients required lower extremity revascularization for leg ischemia, as did 18 (16%) of the controls. Eleven (26%) young patients and 45 (41%) controls died during follow-up (NS). The calculated 5-year survival for young patients was 0.83 (95% CI, 0.71 to 0.95), and it was 0.67 (95% CI, 0.58 to 0.77) for the control subjects (P=.06) (Fig 2⇓).

Kaplan-Meier curves demonstrating survival rates for young patients (Y) and older control subjects (C) compared with the expected survival rate of 45-year-old adults in the general population (expected). Data for survival rate of 45-year-old adults were extrapolated from Reference 22.

Discussion

In 1983, Clagett et al15 reported that patients from their cohort at Walter Reed Army Medical Center with recurrent carotid disease were significantly younger than matched control subjects who did not develop carotid recurrences. The authors suggested that this finding was due either to a more virulent form of CA among young patients or to longer follow-up among younger patients, who survived longer and therefore had a greater opportunity for detection of recurrences. Since then, there have been 33 series of patients with recurrent carotid disease that have examined variables associated with increased risk of recurrence. Only three of these192021 evaluated age as a risk factor for recurrence, but young age at original CEA was not systematically evaluated as a variable. Our studies on premature atherosclerosis in the lower extremity have identified that this is a more progressive form of arterial disease.23 Natural history data on premature CA suggest that disease in this location is equally virulent. After onset of cerebrovascular symptoms, young adults with CA have a higher recurrent stroke and death rate compared with young adults whose cerebrovascular symptoms are due to nonatherosclerotic causes.1012 The effect of CEA in improving late outcome in young patients with CA has not heretofore been examined.

The present data suggest that young patients with cerebrovascular symptoms due to CA have a better outcome after CEA than without intervention. Previous studies have documented a recurrent symptom rate of approximately 43% at 3 to 5 years in untreated patients.1012 Our late recurrent symptom rate of 14% compares favorably with the previously published data, but it is inferior to the late recurrent symptom rate among our older control subjects. Our data suggest that young patients undergoing CEA for CA have a similar rate of progression of lower-extremity atherosclerosis compared with older patients. There was a strong trend toward improved long-term survival in the young patients compared with their older counterparts, but the difference did not reach statistical significance. Optimism is mitigated, however, by comparison with the age-matched population: survival of the young CEA patients in the present study is markedly reduced in comparison with that of similarly aged adults in the general population.22 The high prevalence of recurrent carotid disease in young patients indicates that premature CA is a more virulent form than that affecting the older population and confirms our observations of premature atherosclerosis in other vascular beds.23

The 24% recurrence of hemodynamically significant carotid stenoses in young patients is alarming. Because length of follow-up was similar among young and older subjects, we feel that our results are indicative of the virulence of premature CA, not of the longer follow-up afforded by young age at operation. Eight of 10 young patients developed recurrent carotid stenoses after 2 years; this time course suggests that recurrent atherosclerosis was the likely etiology of the recurrent carotid lesions.23 Other than youth, we are unable to ascribe any other variables to the high rate of recurrence. Commonly accepted risk factors for recurrent carotid disease include small arteries, female sex, and continued cigarette smoking after CEA.15242526 Arterial size measurements were not available in most of our young patients for analysis. Because there is a reported correlation between small arteries and youth,27 it is conceivable that some of the risk for recurrence could be ascribed to arterial size and not to the virulence of the disease process per se. However, since an equal number of young patients with recurrence underwent patch angioplasty and primary closure, the effect of residual internal carotid size does not appear to be a major factor. We are unable to explain why only one woman developed recurrent carotid disease, other than to suggest that premature atherosclerosis may be a stronger risk factor for recurrence than female sex. Since all of our young patients and the majority (91%) of control subjects continued to smoke after CEA, we are unable to determine the impact of continued smoking on recurrence in this study.

There are limitations in this study. Because it is retrospective, a number of recurrences and deaths may have been missed. However, the mean duration of follow-up was similar in study patients and control subjects, and both groups were subjected to similar follow-up assessment. Since protocol patients (controls) were more rigorously followed up and less likely to have had missed events, the differences in recurrence rates between younger patients and older control subjects may have actually been larger than presently reported.

The recurrence rate among our control subjects was lower than that reported by others.242528 However, our results are similar to those of large modern series.2930 Previous reports from our institutions1617 have demonstrated a low incidence of late carotid recurrences; the present results are not different from those previously reported. Even in comparison of our data with those of others, the prevalence of carotid recurrences among our young study patients was higher than would have been expected in populations unselected by age.

The clinical importance of a recurrent carotid stenosis in an asymptomatic young adult is unknown. Only 6 of our 10 young patients with recurrent stenoses demonstrated by duplex ultrasonography had recurrent symptoms. However, it should be pointed out that none of the young patients without recurrent stenoses developed recurrent symptoms. The recurrent symptom rate of 14% in this study may be an underestimate. Among the 4 patients with asymptomatic recurrent stenoses, 2 were lost to follow-up shortly after restenoses were detected. Since recurrent symptoms occurred only in patients with recurrent stenoses, we submit that a carotid recurrence ≥50% should be considered a marker for recurrent symptoms in these young patients. We continue to advocate routine surveillance with duplex ultrasound in these patients. However, we acknowledge that the effectiveness of such an approach remains unproved as a means of preventing strokes in young adults after CEA. A prospective study and an analysis of cost effectiveness would be necessary for validation.

The present data suggest that recurrent carotid stenoses are more likely after CEA in younger patients compared with older counterparts. Close follow-up of these patients with serial noninvasive tests such as duplex ultrasonography may be important to detect recurrences.

Selected Abbreviations and Acronyms

CA

=

carotid atherosclerosis

CEA

=

carotid endarterectomy

CI

=

confidence interval

TIA

=

transient ischemic attack

Acknowledgments

This work was supported in part by American Heart Association, Texas Affiliate, Inc, grant 93R-072.

Footnotes

Presented in part at the 21st International Joint Conference on Stroke and Cerebral Circulation, San Antonio, Tex, January 25-27, 1996.